tbuckley/cabot-search huggingface dataset:
Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication
Authors: Marco Gargaro, Giulia Scalisi, Giorgia Manni, Carlos G. Briseño, Prachi Bagadia, Vivek Durai, Derek J. Theisen, Sunkyung Kim, Marilena Castelli, Chenling A. Xu, Gerd Meyer zu Hörste, Giuseppe Servillo, Maria A. Della Fazia, Giulia Mencarelli, Doriana Ricciuti, Eleonora Padiglioni, Nicola Giacchè, Carolina Colliva, Roberto Pellicciari, Mario Calvitti, Teresa Zelante, Dietmar Fuchs, Ciriana Orabona, Louis Boon, Alban Bessede, Marco Colonna, Paolo Puccetti, Theresa L. Murphy, Kenneth M. Murphy, Francesca Fallarino
Journal: Immunity (2022)

Conventional dendritic cells (cDCs), cDC1 and cDC2, act both to initiate immunity and maintain self-tolerance. The tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is used by cDCs in maintaining tolerance, but its role in different subsets remains unclear. At homeostasis, only mature CCR7+ cDC1 expressed IDO1 that was dependent on IRF8. Lipopolysaccharide treatment induced maturation and IDO1-dependent tolerogenic activity in isolated immature cDC1, but not isolated cDC2. However, both human and mouse cDC2 could induce IDO1 and acquire tolerogenic function when co-cultured with mature cDC1 through the action of cDC1-derived l-kynurenine. Accordingly, cDC1-specific inactivation of IDO1 in vivo exacerbated disease in experimental autoimmune encephalomyelitis. This study identifies a previously unrecognized metabolic communication in which IDO1-expressing cDC1 cells extend their immunoregulatory capacity to the cDC2 subset through their production of tryptophan metabolite l-kynurenine. This metabolic axis represents a potential therapeutic target in treating autoimmune demyelinating diseases.
Abstract 5054: Breast cancer survival analysis with the size of the infiltrative cancer area
Authors: JunYoung Choi, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang
Journal: Cancer Research (2022)

Abstract Background: Analyzing breast cancer prognosis factors is important for survival analysis. In general, the approximate size of the tumor is considered in pathologic staging, but it is not known whether the exact size of the infiltrative cancer area is related to the patients' survival. To analyze the effectiveness of the size of the infiltrative cancer area for survival analysis of patients, we developed a machine learning algorithm that predicts death risk by analyzing clinical data and the actual size of the infiltrative cancer area from hematoxylin and eosin stained whole slide images (WSIs) of breast cancer. Design: To obtain an area of infiltrative cancer, an experienced pathologist conducted annotations using WSIs of breast cancer resection tissue. The data analyzed in this study was from The Cancer Genome Atlas’s breast cancer data set (TCGA-BRCA). There were 871 WSIs labeled with survival events and periods, and several clinical features according to patients including the age at diagnosis, ER, PR, HER2 status, and pathologic TNM stages. We extract the size of the infiltrative cancer area from annotations and incorporate them with clinical features. There existed 53 uncensored data, and we splitted the whole dataset into 8:2 for training/validation. We performed 5-fold cross validation with random sampling. We trained a Cox Regression model with features and compared C-index according to features. Result: The C-index with the infiltrative cancer area for the test set was 0.806. This figure is an improvement of 0.2 from 0.781 without the infiltrative cancer area. The hazard ratio of the infiltrative cancer area was 1.84. The p-value of the infiltrative cancer area was 0.019 for the log-rank test. Conclusion: This result shows that the infiltrative cancer area is a useful feature even in the presence of the TNM stage. Citation Format: JunYoung Choi, Tae-Yeong Kwak, Sun Woo Kim, Hyeyoon Chang. Breast cancer survival analysis with the size of the infiltrative cancer area [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5054.
Abstract 3144: Pleiotrophin drives a pro-metastatic immune niche within breast tumor microenvironment
Authors: Debolina Ganguly, Tuong V. Ngo, Morgan Coleman, Noah Sorrelle, Adrian Dominguez, Jason Toombs, Marcel Schmidt, Fa V. Mora, David G. Ortega, Anton Wellstein, Rolf A. Brekken
Journal: Cancer Research (2022)

Abstract Immune cells in the tumor microenvironment (TME) can impact cancer cell invasion, seeding and colonization of secondary metastatic sites. Our findings show that Pleiotrophin (PTN), a unique and previously under-studied heparin binding cytokine, contributes to inflammation within the TME. PTN appears to be particularly efficient in recruiting neutrophils, which have been reported to cause immune suppression. Consequently, inhibition of PTN pharmacologically or genetically results in lower breast cancer metastasis to lungs and better survival in multiple mouse models of breast cancer. Corroborating our mouse studies, we have found that higher PTN expression in breast cancer patient plasma correlates with poor prognosis. Concurrently, stage IV breast cancer patients that have lower PTN expression have a highly significant survival advantage (median survival 78.27 months) over patients expressing high levels of PTN (median survival 27.5 months). Additionally, we have also found PTN positive cancer cells are enriched in metastatic lesions suggesting that PTN-high cancer cells are more successful at colonizing and surviving at the secondary site. Uncovering the function of PTN in these unique cancer cells might have a major impact in the clinical setting. Overall, our data suggests that PTN is important in driving a pro-metastatic immune niche within the TME that promotes tumor cell escape from the primary tumor and survival of metastatic cancer cells in secondary sites. Additionally, our studies highlight that inhibition of PTN has potential to reduce metastatic burden in breast cancer and suggest that future studies testing the combination of PTN inhibition with standard chemotherapy or immune therapy are warranted. Citation Format: Debolina Ganguly, Tuong V. Ngo, Morgan Coleman, Noah Sorrelle, Adrian Dominguez, Jason Toombs, Marcel Schmidt, Fa V. Mora, David G. Ortega, Anton Wellstein, Rolf A. Brekken. Pleiotrophin drives a pro-metastatic immune niche within breast tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3144.
Abstract 6087: Evaluation of intra-tumor heterogeneity by single-cell copy number profiling of circulating multiple myeloma cells using Shannon index
Authors: Alberto Ferrarini, Claudio Forcato, Valentina del Monaco, Mario Terracciano, Marianna Garonzi, Massimiliano Pellicano, Genny Buson, Francesca Fontana, Paola Tononi, Nicolo Manaresi
Journal: Cancer Research (2022)

Abstract Tumors develop through an evolutionary process in which genomic lesions accumulate in different coexisting subclones leading to intra-tumor heterogeneity (ITH). ITH allows the tumor to adapt to microenvironments and to resist therapies and has been shown to be a prognostic marker. In this work we show the characterization of ITH in Multiple Myeloma (MM) at single cell resolution from a pool of Circulating Multiple Myeloma Cells (CMMCs) and we study the relationship between number of sampled cells and diversity detected. Peripheral blood was collected from 3 patients affected by MM. Using CellSearch® system, blood was enriched for target CMMCs, with immuno-magnetic selection of CD138+, and immunofluorescently stained cells, positive for CD38-PE, DAPI and negative for CD45/CD19-APC, were enumerated. The samples were then analyzed and CMMCs were isolated with DEPArray platform. The DNA of each single cell (n=261) was amplified with Ampli1™ WGA kit and the WGA output was used for genome-wide single cell copy number alteration analysis with Ampli1 LowPass kit. Copy number profiling revealed from 2 to 3 coexisting subclones per patient, with minor clones size going from 6.5% to 33%. ITH was assessed by determining the Shannon index, which showed a range of values from 0.44 (low diversity) to 1.01 (high diversity) depending on source sample. We evaluated the effect of number of cells/profiles on Shannon index by bootstrapping (200 times) a number of copy number profiles ranging from 2 to the total number of profiles available per patient. Results showed that the mean Shannon index almost reaches a plateau at 15-20 cells/profiles in the case of lower diversity samples and at about 30 cells/profiles for the highest diversity sample. Moreover, as few as 10 cells allowed to differentiate low vs. high diversity samples. Cell enrichment and sorting by CellSearch and DEPArray platforms allow to quantify ITH at diversity level with high precision even from a limited number of initial single-cells and provide a promising method to objectively measure heterogeneity, as required in order to study its clinical implications. Citation Format: Alberto Ferrarini, Claudio Forcato, Valentina del Monaco, Mario Terracciano, Marianna Garonzi, Massimiliano Pellicano, Genny Buson, Francesca Fontana, Paola Tononi, Nicolo Manaresi. Evaluation of intra-tumor heterogeneity by single-cell copy number profiling of circulating multiple myeloma cells using Shannon index [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6087.
Abstract 5968: Ethnodyne Visio™ affects EGFR signaling in breast cancer
Authors: Rishab Rajeev Samant, Rajeev Samant
Journal: Cancer Research (2022)

Abstract Breast Cancer (BC), the most common form of female cancer, is one of the most extensively studied diseases. Metastasis is the process by which a cancer cell travels to another part of the body and starts to multiply. This detrimental occurrence is one of the primary forms of disease relapse in cancer patients and accounts for an estimated 90 percent of cancer deaths. Ethnodyne Visio™ is a new drug for Age-Related Macular Degeneration (AMD), the primary cause for blindness in people 65 and older. It is a mixture of phytochemicals Withaferin A, Gallic Acid, and Bacopaside I. However, the exact mechanism of action of Ethnodyne Visio™ is not known. Macular Degeneration occurs in two primary forms: wet and dry. Wet Macular Degeneration shows surprising similarities with metastatic Breast Cancer in terms of their progression and causation. As both diseases evolve, the retina (in the case of Wet AMD) and the tumor (in the case of BC) secrete Vascular Endothelial Growth Factor (VEGF) to encourage vascular development. In Wet AMD, this new and unregulated vascular growth, or angiogenesis, causes “leaky” blood vessels that allow fluid to enter the retina, ultimately causing blindness. In BC, this blood vessel growth provides a means for the tumor to obtain nutrients as well as disseminate metastatic cells. We determined if there exists any easily accessible nutraceuticals possessing effective antiangiogenic properties. We used CAMs (chick chorioallantoic membrane), grown ex-ovo, to study angiogenesis. We found that Ashwagandha (Withaferin A) blocked angiogenesis of CAMs by 67%. Taking clues from these observations, we wanted to determine possible molecular signaling mechanisms triggered by Ethnodyne Visio™ that may counter progression of BC. We hypothesized that Ethnodyne Visio™ may have anti-angiogenic properties. Using multiple online gene association platforms, we compiled a list of transcriptomic changes caused by Withaferin A, Gallic Acid, and Bacopaside I on breast tumor cells. A g:Profiler analysis of the combined transcriptomic changes revealed Epidermal Growth Factor Receptor (EGFR) signaling as a downstream target of the components of Ethnodyne Visio™. Our analysis reveals that Ethnodyne Visio™ potentially regulates VEGF signaling through the EGFR pathway. Citation Format: Rishab Rajeev Samant, Rajeev Samant. Ethnodyne Visio™ affects EGFR signaling in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5968.
Abstract 4054: Investigation of antitumor activity induced by antifungal agents in human metastatic melanoma cells
Authors: Lukas R. Jira, Hattie M. Foster, Hannah K. Hall, David W. Koh
Journal: Cancer Research (2022)

Abstract Melanoma remains as the most aggressive and lethal form of skin cancer for which new therapies are still needed. Current treatment options include conventional chemotherapy, immunotherapy, and targeted therapy. Disadvantages of these therapies, as well as other factors such as refractiveness, have contributed to poor outcomes in melanoma patients. Antifungal drugs potentially represent a novel class of anticancer agents. Our objective here was to analyze the ability of these agents to eradicate primary human metastatic melanoma cells. Antitumor effects were investigated using cell growth and proliferation assays, flow cytometry (FACS), and cell death assays. Wild-type human melanoma cell lines or those possessing the BRAF V600E mutation or the NRAS Q61R mutation were analyzed. Clotrimazole treatment led to profound decreases in cell growth in wild-type and NRAS mutant melanoma cells. Significant, but lesser effects were observed in BRAF mutants. However, treatment with econazole caused substantial reductions in cell growth in wild-type and BRAF mutant cells. These results were corroborated by cell death analyses and FACS, where clotrimazole treatment caused greater than 80% cell death in wild-type and NRAS mutant cells, while econazole caused greater than 75% cell death in BRAF mutants. Taken together, these preliminary studies indicated that clotrimazole and econazole were effective in inducing antitumor effects in human metastatic melanoma cell lines, but with differing degrees of efficacy. This data suggests that melanoma tumors of each known genotype can potentially be treated with antifungal agents. In conclusion, this study demonstrated the ability of antifungal agents to successfully treat human metastatic melanoma cells. Since each agent displayed differential effects for each type of mutation, it is possible that these antifungal agents affect different molecular targets in each melanoma cell line. These antifungal agents thus appear to be potential alternative treatments, as well as affordable and widely accessible therapies, for melanoma patients in the future. Citation Format: Lukas R. Jira, Hattie M. Foster, Hannah K. Hall, David W. Koh. Investigation of antitumor activity induced by antifungal agents in human metastatic melanoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4054.
Abstract 3640: Adipocyte age dependent metabolic programming dictates melanoma metastatic burden and tropism
Authors: Shilpa Gurung
Journal: Cancer Research (2022)

Abstract The aged skin microenvironment and aged fibroblasts contribute to melanoma progression. A key hallmark of skin ageing is the loss of subcutaneous fat. Because previous work has established that lipids contribute to melanoma invasion and proliferation, we studied whether aged adipocytes contribute to the poor outcome of aged patients. We compared the distinct lipid secretory profile of young and aged human subcutaneous adipocytes, and discovered young and aged adipocytes contribute different lipids to the melanoma microenvironment, activating aged-dependent signaling pathways and driving distinct metabolic programms in melanoma cells. To test how aged and young adipocytes affect melanoma, we obtained human preadipocytes from donors of different ages and differentiated them to functional adipocytes in vitro. We studied the morphological, transcriptomic, proteomic, and lipid profile of adipocytes by age, then exposed melanoma cells to the young or aged adipocyte secretome. We observed melanoma cells exposed to young adipocyte secretome increased the rate of proliferation, invasion, and migration compared to melanoma cells exposed to aged adipocyte secretomes. This effect was linked to a greater amount of total lipids secreted by young adipocytes, as well as a unique ratio of lipids by age, which were taken up by melanoma cells. Critically, lipid transfer led to distinct signaling pathway activation and metabolic reprogramming. In vivo, these differences led to a greater rate of metastasis and distinct tropism of melanoma cells exposed to aged or young adipocyte secretomes. Finally, we systematically tested the contribution of differentially secreted lipids by age and identified the specific lipids that function as signaling molecules to switch metabolic dependencies and fuel proliferation, invasion, and migration of melanoma cells Citation Format: Shilpa Gurung. Adipocyte age dependent metabolic programming dictates melanoma metastatic burden and tropism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3640.
Abstract 4022: ERK1/2 inhibitor ulixertinib demonstrates activity in atypical (non-V600) BRAF mutant models
Authors: Deborah Knoerzer, Anupama Reddy, Adnan Derti, Caroline M. Emery
Journal: Cancer Research (2022)

Abstract Atypical BRAF (non-V600) alterations comprise approximately half of all BRAF mutations in cancer and can be categorized according to characteristics of molecular signaling (either Class II or III). Atypical BRAF alterations are rare (approximately 3% across all human cancers) and there are currently no approved therapies for this indication. As next-generation sequencing becomes standard clinical practice, oncologists are frequently identifying atypical BRAF alterations in their patients’ tumors. The efficacy of the first-in-class ERK1/2 inhibitor, ulixertinib (BVD-523), was assessed across 10 patient-derived xenograft (PDX) models, which harbored class II or III BRAF alterations (5 models with type II alterations, 4 models with class III, and 1 model with both class II and III). Responses ranging from robust regression to moderate tumor growth delay were observed in 9/10 models. RNA sequencing was performed on tumors from the vehicle-treated and ulixertinib-treated groups with three replicates per PDX model. The samples were collected 2 hours after the last dose of treatment. Expression of the mutant BRAF alleles was readily confirmed from RNA-seq data in all PDX models. In addition, gene expression analysis showed differential expression of MAPK pathway genes in responders compared to the non-responders. In summary, ulixertinib has exhibited strong pre-clinical activity in a variety of patient-derived xenograft models with atypical BRAF alterations. Ulixertinib has FDA fast-track designation for patients with solid tumors, other than CRC, harboring specific BRAF mutations (G469A, L485W, or L597Q) and is currently under clinical evaluation in patients with tumors harboring any atypical BRAF alteration (NCT04488003). Citation Format: Deborah Knoerzer, Anupama Reddy, Adnan Derti, Caroline M. Emery. ERK1/2 inhibitor ulixertinib demonstrates activity in atypical (non-V600) BRAF mutant models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4022.
Abstract 596: IOH-001, a novel CD47/PD-L1 bispecific antibody, enhances anti-tumor activity in solid tumors
Authors: Jeong-kook Kim, A-Ra Jeon, Jihyun Park, Ji Yea Choi, Ji Eun Park, Sun Kwang Song, Ji Hye Choi, Heewook Shin, Ji Hye Lee, Ji Hye Yun, Yoen Hee Ahn, Heung Tae Kim
Journal: Cancer Research (2022)

Abstract Background: The survived cancer cells after cytotoxic chemotherapy are known to promote immune evasion phenotype by increasing the expression of PD-L1 and CD47. Targeting of CD47 and PD-L1 is predicted to overcome immune evasion by coordinately restoring each innate and adaptive immunity. IOH-001, a CD47/PD-L1 dual-targeting bispecific antibody, has been shown to activate immune cells in tumor microenvironment by blocking PD-1/PD-L1 signals that inhibit cytotoxic T-cells, while also blocking interaction with CD47/SIRPa between cancer cells and macrophages. We have investigated whether IOH-001 inhibits tumor growth via co-targeting tumor cells or not. Methods: To assess the function of IOH-001, a series of in vitro functional assays including cell surface binding, antibody-dependent cellular cytotoxicity (ADCC), phagocytosis assays and mixed lymphocyte reaction (MLR) assay were performed compared with the parent antibody. In vivo efficacy of IOH-001 was tested in colon cancer mouse models with human genes KI. Results: IOH-001 has been shown to be bound strongly to various types of PD-L1/CD47-expressing cancer cells including the ones in solid and hematological cancers. In most cancer cells, IOH-001 was demonstrated to have a lower EC50 than the parental antibodies and to be bound in a dose-dependent manner as well. Interestingly, IOH-001 also has shown the selectivity to bind only to cancer cells even under the conditions of co-culturing RBC and cancer cells. IOH-001 has induced phagocytosis of cancer cells by human blood CD14+ monocyte-derived macrophages. Since IOH-001 is an IgG1 type antibody, ADCC and IFN-r expression have been increased compared with the parental antibodies. Consistent with the in vitro data, IOH-001 has more strongly suppressed tumor growth than the combination treatment of the parental antibodies in a dose-dependent manner in syngeneic animal models. Moreover, the tumor of the CR mouse has been identified not to be re-generated in the re-challenge model. Conclusion: IOH-001, dual-blockage of anti-CD47 and anti-PD-L1, has shown the benefits in treating some solid tumors. Bispecific antibody IOH-001 is more likely to work better in targeting tumor cells than the combination of anti-CD47 and anti-PD-L1. Preclinical efficacy results of IOH-001 provide a strong rationale for assessing therapeutic potential in clinical studies. Citation Format: Jeong-kook Kim, A-Ra Jeon, Jihyun Park, Ji Yea Choi, Ji Eun Park, Sun Kwang Song, Ji Hye Choi, Heewook Shin, Ji Hye Lee, Ji Hye Yun, Yoen Hee Ahn, Heung Tae Kim. IOH-001, a novel CD47/PD-L1 bispecific antibody, enhances anti-tumor activity in solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 596.